Jeffery A. Hobden, PhD
Pharmacology – Antimicrobial Agents
Chapter 47, Goodman & Gilman
March 2009
Isoniazid
I. Chemistry
A. hydrazide of isonicotinic acid (related to nicotinic acid or vitamin B3)
B. also known as INH (for isonicotinic hydrazide)
C. water soluble, totally synthetic
II. Effect on Microbes
A. spectrum of coverage– Mycobacterium tuberculosis, M. kansasii
B. mechanism of action
1. INH is a prodrug that requires a catalase-peroxidase for activation 2. bactericidal for rapidly dividing cells, bacteristatic for resting bacilli
3. prevents synthesis of mycolic acids
C. mechanism s of resistance - mutation in catalase-peroxidase gene
III. Pharmacology of Isonaizid
A. Absorbance – given orally or parenterally
B. Fate after absorption
1. readily diffusible into all bodily cells and fluids
2. penetrates well into caseous material
C. Excretion – kidneys as a set of inactive metabolites (mostly as acetylisoniazid)
1. rate of inactivation depends on levels and activity of NAT2, the enzyme that acetylates INH
2. fast acetylators are Inuit and Japanese, have 30-50% less active drug than slow acytelators
3. slow acetylators are most Scandinavians, Jews, and North African
Caucasians
4. In the U.S., about half are fast acetylators
IV. Pharmacology of Select Agents – only one in its class
V. Therapeutic Uses – treatment of all forms of tuberculosis
VI. Toxicity/Contraindications
A. rash and fever (uncommon)
B. jaundice (rare)
C. peripheral neuritis (rare) – preventable if vitamin B6 is co-administered
The Rifamycins
I. Chemistry
A. natural products ofAmycolatopsis mediterranei (filamentous soil bacteria) and semisynthetic derivatives
1. rifabutin and rifapentine are natural products
2. rifampin (aka rifampicin in US) is a semisynthetic derivative
B. complex macrocyclic antibiotics
II. Effect on Microbes
A. spectrum of coverage – broad spectrum
B. mechanism of action
1. inhibits DNA-dependent RNA polymerase
2. bactericidal
C. mechanism(s) of resistance - altered target
III. Pharmacology of rifamycins
A. Absorbance
1. administered orally
2. occurs mostly in gastrointestinal tract
3. interference by aminosalicylates (asprin)
B. Fate after absorption
1. widely distributed throughout the body into tissues and secretions (can cause orange-red pee or stools, saliva and tears)
2. drug is acetylated depending on race
C. Excretion – into the bile
IV. Pharmacology of Select Rifamycins
A. rifampin
1. antimicrobial spectrum – broad
2. absorption - gastrointestinal
3. fate after absorption – wide distribution
4. excretion - bile
5. therapeutic uses
a) combined with INH to treat TB
b) chemoprophylaxis for meningococcal disease
c) combined with beta-lactam for staph enocarditis and osteomylitis
B. rifabutin
1. antimicrobial spectrum – broad
2. absorption - same as rifampin
3. fate after absorption – wide distribution
4. excretion - bile
5. therapeutic uses
a) used to treat TB in HIV patients on HAART
b) works better against MAC than rifampin
C. rifapentine
1. antimicrobial spectrum – broad
2. absorption - same as rifampin
3. fate after absorption – wide distribution, longer half life than rifampicin or rifabutin
4. excretion - bile
5. therapeutic uses – used to treat TB in HIV patients on HAART
V. Therapeutic Uses – see above for individual agents
VI. Toxicity/Contraindications
A. side effects associated with rifampin
1. flu-like symptoms if administered less than twice weekly or in daily doses of 1.2 grams or greater (common)
a) fever
b) chills
c) myalgias
2. decreases half-life of a number of other drugs by inducing several cytochrome oxidases (CYP1A2, 2C9, 2C19, and 3A4). Affected drugs include (among others):
a) HIV protease and non-nucleoside reverse transcriptase inhibitors
b) corticosteroids
c) oral contraceptives
3. the usual collection of systemic complaints (uncommon)
a) gastrointestinal disturbances
b) nervous system – headaches, dizziness, etc.
c) hypersensitivity reactions
4. urine, tears, and sweat may turn orange
B. side effects associated with rifambutin
1. induces CYPs like fifampicin, but not as bad
2. polymalgia, pseudojaundice, anterior uveitis
Ethambutol
I. Chemistry – water soluble and heat stable
II. Effect on Microbes
A. spectrum of coverage – Mycobacterium tuberculosis, M. kansasii, MAC
B. mechanism of action – inhibits arabinosyl transferases involved in cell wall synthesis
C. mechanisms of resistance - mutation in arabinosyl transferase gene
III. Pharmacology of Ethambutol
A. Absorbance – given orally (80% absorbed in GI tract)
B. Fate after absorption – 75% of the dose remains unchanged
C. Excretion – kidneys
IV. Pharmacology of Select Agents – only one in its class
V. Therapeutic Uses – tuberculosis
VI. Toxicity/Contraindications
A. optic neuritis (uncommon)
1. dose dependent (more drug = worse symptoms)
2. diminished visual acuity + inability to tell red from green
B. miscellaneous symptoms (rare) – rash, itching, GI upset, etc.
Pyrazinamide
I. Chemistry – synthetic pyrazine analog of nicotinamide
II. Effect on Microbe
A. spectrum of coverage- Mycobacterium tuberculosis
B. mechanism of action
1. bactericidal at a weakly acidic pH (as in an acidic macrophage vacuole)
2. inhibits fatty acid synthase I gene involved in mycolic acid synthesis C. mechanism of resistance – mutation of target gene
III. Pharmacology of Pyrazinamide
A. Absorbance – given orally (absorbed in GI tract) with excellent penetration
B. Fate after absorption – hydrolyzed to pyrazinoic acid, then hydroxylated
C. Excretion – kidneys
IV. Pharmacology of Select Agents – only one in its class
V. Therapeutic Uses – tuberculosis
VI. Toxicity/Contraindications
A. hepatotoxicity (uncommon)
B. hyperuricemia resulting in acute episodes of gout (rare)